Aromatic bromides and iodides are versatile reagents that can be converted to a wide variety of materials. For over 50 years, substitution reactions of aromatic halides have been used in organic synthesis. These reactions give compounds containing new carbon-carbon or carbon-heteroatom bonds in high yields. Furthermore, a series of reactions that are characteristic for aromatic iodides alone has been discovered.
Several methods for preparing various classes of aromatic halides have been published in monographs, journal reviews and patents. Representative processes for preparing aromatic halides are: direct aromatic halogenation in which a hydrogen atom is substituted by a halogen atom using bromine or iodine [Braendlin, H. P. and McBee, E. T., “Friedel-Crafts and Related Reactions”, Ed. Olah, G., Interscience Publisher, NY, 1964, Vol. 111, part 2, p 1517]; and the Sandmeyer reaction in which an amino group is substituted by a halogen atom via diazonium salt [“The Chemistry of Diazonium and Diazo Groups”, Ed. Patai, S., J. Wiley, NY. 1978, part 1, p 288].
One drawback to direct aromatic halogenation has been the formation of other isomers as impurities. Direct iodination with I2 is also possible using a mixture of nitric acid and sulfuric acid. However, the use of strong acids is extremely undesirable to the highly substituted arenes and heterocyclic compounds.
Since aromatic amines are generally more economical, most methods for preparing highly substituted aromatic halides have centered on improving the Sandmeyer reaction. The Sandmeyer reaction involves a 2-step process of diazotization followed by halogenation. First, the amino group is converted to diazonium salt by reacting it with nitrite ions under acidic conditions, and the nucleophilic halide ion is then substituted at the same position. The typical Sandmeyer reaction may be carried out in the presence of copper halide as a nucleophile (Org. Syn. Coll. Vol. 3, 1955, 185). However, the discharge of excess copper salt may cause environmental pollution. In addition, since the stability of diazonium salt is the most important factor in the Sandmeyer reaction, special conditions such as a low reaction temperature and filtration are required in the process.
Considering the wide application of aromatic halides, it is required that the innovation of a synthetic process of the aromatic halides in a low cost and simple while minimizing waste byproducts. Some modified Sandmeyer reactions that involve diazonium salt have been developed to achieve simplicity and low cost. Unlike methods that require sodium nitrite and acidic conditions to prepare diazonium salt, isoamyl nitrite is a useful and mild in situ diazotizing agent for the preparation of aromatic iodides (Smith, W. B., Ho, O. C., J. Org. Chem., 1990, 55, 2543). Although the prior art is especially attractive when aromatic amines bear acid-labile groups and/or the reaction requires neutral conditions, it can be difficult to separate the product from excess diiodomethane.
In order to achieve the low cost of manufacturing and the decrease of environmental problems, the following factors should be considered:
(1) to develop diazotization for a one step reaction in situ; and
(2) to develop an active nucleophile which can replace CuBr, I2 or CH2I2.